Type 2 diabetes is often treated by drugs designed to suppress hepatic glucose production. One class of drugs having this capability are drugs that inhibit glycogen phosphorylase, the enzyme which mediates the breakdown of glycogen. Such glycogen phosphorylase inhibitors (GPIs) inhibit the liver's production of glucose by inhibiting this enzyme's ability to catalyze glycogonolysis, or the breakdown of the glucose polymer glycogen. A particularly effective GPI is 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide, having the structure
and, for ease of reference, hereinafter referred to as Drug A. See PCT Application WO 96/39385 A1.
Although most known classes of GPIs have relatively high aqueous solubility and correspondingly high bioavailability when dosed orally, Drug A is a sparingly soluble drug, the lowest energy crystalline form of which has an aqueous solubility of from about 0.06 to about 0.08 mg/mL. Because of such low aqueous solubility, when tested in vitro Drug A has low maximum concentration (cmax) and area under the concentration vs. time curve (AUC) values in a given environment of use. In addition, when the lowest energy crystalline form of the drug is tested in vivo by orally dosing, the cmax of Drug A in the blood plasma, its AUC and its relative bioavailability are all low. Thus, it would be desirable to enhance the relative bioavailability of Drug A.